PL181582B1 - Skin sticking plaster and method of administering sole 17-deacetyl norgestimate or together with estrogen - Google Patents

Abstract

1. A skin patch for preventing ovulation in a woman, comprising a coating layer and a matrix layer beneath the coating layer, characterized in that the matrix layer consists of a mixture of 17-deacetylnorgestimate, a pressure-sensitive adhesive containing at least silicone or polyisobutylene and possibly an agent that enhances skin permeability. 18. A skin patch for female hormone replacement therapy, comprising a coating layer and a matrix layer beneath the coating layer, characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, estrogen, a pressure-sensitive adhesive containing at least silicone or polyisobutylene and, optionally, an agent that enhances skin permeability. PL PL PL PL PL PL PL PL

Description

The invention relates to a skin patch for preventing ovulation in a woman and for carrying out hormone replacement therapy.

Mixtures of norgestimate (Ngm) and ethinylestradiol (EE) are given orally to women as contraceptive. Bringer J., Am. J. Obstet. Gynecol. (1992) 166: 1969-77. McGuire, J.C. et al, Am. J. Obstet. Gynecol. (1990) 163: 2127-2131 suggest that orally administered Ngm is metabolized to 17-deacetylnorgestimate (17-d-Ngm), 3-ketonorgestimate and levonorgestrel (Lng), and that these metabolites may contribute to the pharmacological response resulting from oral administration of the drug.

Chien et al. US Patent No. 4,906,169, describes skin patches for the co-administration of estrogens and progestins to women as contraceptives. EE is listed as one of the estrogens that can be administered from the patch, and Ngm and Lng are listed as administrationable progestins.

There are no known descriptions of transdermal or other administration of 17-d-Ngm alone or together with some estrogen.

The invention proposes kits of agents for preventing ovulation or carrying out hormone replacement therapy by administering to women an effective amount of the active ingredient 17-deacetyl-norgestimate alone or in combination with an ovulation-suppressing estrogen.

The skin patch for preventing ovulation in a woman according to the invention comprises a coating layer and a matrix layer under the coating layer and is characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, a pressure-sensitive adhesive containing at least silicone or polyisobutylene, and optionally an agent enhancing skin permeability.

Preferably, the patch contains a dose of 17-deacetyl-norgestimate in an amount of 175 to 300 pg / day.

Preferably, polyisobutylene is included as the pressure-sensitive adhesive.

Preferably the matrix layer comprises a skin permeation enhancer, even more preferably it is selected from the group consisting of C ₁₂ to C ₁₈ aliphatic alcohol lactate esters, oleic acid and PGML, most preferably lauryl lactate.

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According to another embodiment of the invention, a skin patch for preventing ovulation in a woman comprises a coating layer and a matrix layer beneath the coating layer, and is characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, an estrogen, a pressure-sensitive adhesive containing at least silicone. or polyisobutylene and optionally a skin permeation enhancer.

Preferably, the plaster comprises polyisobutylene as the pressure-sensitive adhesive.

Preferably, the matrix layer comprises a skin permeation enhancer.

Preferably the patch comprises estradiol as estrogen, especially ethinylestradiol or 17-β-εstradiol.

When the estradiol is ethinylestradiol, most preferably the patch comprises a dose of 17-deacetyl estradiol in an amount of 175 to 300 pg / day and an amount of ethinyl estradiol in an amount of 10 to 35 pg / day.

When the estradiol is 17-3 estradiol, most preferably the patch comprises a dose of 17-deacetylnorgestimate in an amount of 175 to 300 pg / day and a dose of 17-β-estradiol in an amount of 30 to 150 pg / day.

In a particularly preferred case, the patch comprises ethinyl estradiol or 17-β-estradiol and a skin permeation enhancer selected from the group consisting of lactate esters of C ₁₂ to C ₁₈ aliphatic alcohols, oleic acid and PGML, especially lauryl lactate.

Another embodiment of the invention is a skin patch for carrying out hormone replacement therapy of a woman comprising a coating layer and a matrix layer beneath the coating layer and characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, an estrogen, a pressure-sensitive adhesive containing at least silicone or polyisobutylene, and optionally a skin permeation enhancer.

Preferably, the plaster comprises polyisobutylene as the pressure-sensitive adhesive.

Preferably, the matrix layer comprises a skin permeation enhancer.

Preferably the patch comprises estradiol as estrogen, especially ethinylestradiol or 17-β-estradiol.

When the estradiol is ethinylestradiol, most preferably the patch comprises a dose of 17-deacetyl estradiol in an amount of 175 to 300 pg / day and an amount of ethinyl estradiol in an amount of 10 to 35 pg / day.

When the estradiol is 17-β-estradiol most preferably the patch contains a dose of 17-deacetylnorgestimate in an amount of 175 to 300 pg / day and a dose of 17-beta-estradiol in an amount of 30 to 150 pg / day.

In a particularly preferred case, the patch comprises ethinyl estradiol or 17-p-estradiol and a skin permeation enhancer selected from the group consisting of lactate esters of C ₁₂ to C ₁₈ aliphatic alcohols, oleic acid and PGML, especially lauryl lactate.

According to another embodiment of the invention, the skin patch for preventing ovulation in a woman comprises a coating layer and a matrix layer beneath the coating layer and is characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, a pressure-sensitive polyisobutylene binder and polyvinylpyrrolidone.

The skin patches of the invention provide contraceptive protection for women. They are also adapted to hormone replacement therapy.

The patches are intended to be delivered continuously to the skin with 17-d-Ngm and optionally estrogen over an extended period of time, typically 1-7 days, especially 7 days.

When the patch is used for contraception, it is usually placed on the skin on the fifth day of the menstrual cycle and removed if necessary after 21 days of wear. For example, for the 7-day patch, three patches should be used to deliver the drug (s) over a 21-day period. If necessary, a placebo patch can be used after five days of the next menstrual cycle. This rule is repeated for each menstrual cycle.

Both 17-d-Ngm and estrogen inhibit ovulation, although this has been done in different ways.

17-d-Ngm inhibits the release of luteinizing hormone (LH), while the predominant effect of estrogen is the release of follicle stimulating hormone (FSH). Thus, when a mixture of 17-d-Ngm and estrogen is administered according to the invention, ovulation is prevented by inhibiting the ovulation stimulant and / or by inhibiting the development of ovarian follicles. 17-d-Ngm-administration is presumed to be advantageous over the parent compound (Ngm)

181 582 or other metabolites thereof, as 17-d-Ngm inhibits little or no androgen activity.

The effective dose of 17-d-Ngm to inhibit ovulation is usually in the range of from about 150 to about 350 pg / day, preferably from about 175 to about 300 pg / day, and more preferably from about 175 to about 250 pg / day. The patches of the invention typically have a base surface (i.e. a skin diffusive contact surface) in the range of between 10 and 50 cm ² . The effective amount of estrogen to inhibit ovulation depends on the type of estrogen co-administered. For example, when the estrogen is ethinylestradiol, the dose should usually be at least 10 pg / day, preferably from about 10 to 35 pg / day and most preferably about 20 pg / day. The patches should contain sufficient amounts of 17-d-Ngm and estrogen, when the latter is present, to obtain such daily doses for the intended duration of use. Such dosages of ethynylstradiol range from about 20 µg / day to about 200 µg / day, and preferably from about 30 µg / day to 150 µg / day.

The patches of the present invention have a matrix or monolithic layered construction. These types of skin patches are well known. They include a matrix layer of the drug (s) mixed with a pressure-sensitive adhesive and a coating layer. The second matrix is the reservoir of the drug and the means by which the patch is attached to the skin. Before use, the plaster must also contain a non-release boundary layer.

The coating layer is impermeable to the drug and other matrix components and forms the top surface of the patch. It can be made as a single polymer layer or film, or it can be a laminate of one or more polymer layers and a metal foil. Examples of suitable polymers for making coating films are polyvinyl chloride, polyvinylidene chloride, polyolefins such as ethylene vinyl acetate copolymers, polyethylene and polypropylene, polyurethane, and polyesters such as polyethylene terephthalate.

The pressure-sensitive matrix binder typically should be a polyacrylate solution, silicone, or polyisobutylene (PIB). Such tackifiers are well known in the art of skin patch manufacture. See, e.g., Handbook of Pressure Sensitive Adhesive Technology, 2nd Edition (1989) Van Nostrand, Reinhold.

The polyacrylate solution as a pressure-sensitive binder is prepared by copolymerizing one or more acrylate monomers (the term "acrylates" means both acrylates and methacrylates), one or more modified monomers and one or more functional group-containing monomers in an organic solvent. The acrylate monomers used in the preparation of these polymers are typically alkyl acrylates of 4 to 17 carbon atoms, with 2-ethylhexyl acrylate, butyl acrylate and isooctyl acrylate being preferred. Modified monomers are usually included to alter the properties of the polymer. Suitable monomers for this purpose include vinyl acetate, ethyl acrylate and methacrylate, and methyl methacrylate. Functional group-containing monomers provide sites for cross-linking. The functional groups of these monomers are preferably carboxyl; hydroxyl or combinations thereof. Examples of monomers providing such groups are acrylic acid, methacrylic acid, and hydroxyl-containing monomers such as hydroxyethyl acrylate. Polyacrylic binders are preferably crosslinked with a crosslinker to improve their physical properties (i.e. creep and shear strength). The cross-link density should be low as a high degree of cross-linking can adversely affect the adhesive properties of the polymer. Examples of crosslinkers are given in US Patent No. 5,393,529. Pressure sensitive polyacrylate solution binders are commercially available under the trade names GELVA ™ and DURO-ΤΑΚ ™ from 3M.

Polyisobutylene (PIB) binders are mixtures of high molecular weight (HMW) PIB and low molecular weight (LMW) PIB. Such mixtures are described in the art, e.g. in PCT / US91 / 02516. The molecular weight of the HMW PIB should typically be in the range of about 700,000 to 2,000,000. Da, while the typical range of the LMW PIB molecular weight range would be 35,000 to 60,000. The weights reported here are

181,582 molecular weights are weight average molecular weights. The weight ratio of HMW PIB to LMW PIB in the binder should typically be in the range from 1: 1 to 1:10. The polyisobutylene binder should typically also include a component such as polybutene oil and high Tg and low molecular weight aliphatic resins such as ESCOREZ ™ available from Exxon Chemical. Polyisobutylene polymers are commercially available under the trade name VISTANEX ™ from Εχχοη Chemical.

The silicone binders that can be used to form the matrix are typically high molecular weight polydimethylsiloxanes or polydimethyldiphenylsiloxanes. Silicone adhesive formulations that are suitable for skin patches are described in US Patent Nos. 5,232,702, 4,906,169, and 4,951,622.

Estrogens which can be mixed with 17-d-Ngm in the matrix include 17-J-estradiol and its esters as well as estradiol valerate, estradiol cypionate, estradiol acetate, estradiol benzoate and EE. EE is the favored estrogen for use in a mixture with 17-d-Ngm. The EE / 17-d-Ngm mixture may result in the formation of such favorable metabolic parameters of blood serum as an increase in the content of high-density lipoproteins and a reduction in the ratio of the content of low-density lipoproteins to the content of high-density lipoproteins.

In addition to the pressure-sensitive adhesive, the 17-d-Ngm and optionally estrogen matrix should typically contain a sufficient amount of a permeation enhancer to increase the permeation of 17-d-Ngm and estrogen through the skin and achieve flux in the above-described compartments. Examples of skin permeability enhancers which mogąbyć incorporated in the matrix, sąopisanewpatentachUSAnr5,059,426,4,973,468,4,906,463 and 4,906,169 and include, but are not limited to: lactate esters of aliphatic alcohols C ₁₂ to C _18, lauryl lactate, oleic acid and PGML. The amount of permeation enhancer contained in the matrix depends on the type of agent (s) used. In most cases, the content of the permeation enhancer should be 1 to 20% by weight of the matrix.

The matrix may also contain other additives depending on the type of binder used. For example, substances such as polyvinylpyrrolidone (PVP), which inhibits crystallization of the drug, hygroscopic agents that extend the service life, or additives that improve the physical properties (e.g. cold flow) or adhesion (e.g. adhesion, separation strength) of the matrix, may be added.

The above-described patches are also suitable for the carrying out of hormone replacement therapy. When the matrix is used for hormone replacement therapy, it is made to provide an effective amount of 17-d-Ngm and estrogen needed for this purpose. The matrix and thus the patch is designed to provide from about 150 to about 350 pg / day, and preferably from about 175 to about 300 pg / day 17-d-Ngm co-administered with from about 5 to about 45 pg / day and preferably from about 10 to about 35 pg / day ethinyl estradiol. In an alternative embodiment of the invention the patch should administer from about 200 to about 350 pg / day, and preferably from about 175 to about 300 pg / day 17-d-Ngm co-administered with from about 20 to about 175 pg / day, and preferably from about 30 to about 150 pg / day of 17-β-estradiol. The patch is used for 7 days and the action is repeated with a new patch (for 7 days) for the duration of treatment.

The patches according to the invention can be produced by known methods of making skin patches. In general, the method involves making a matrix (e.g., mixing together the binder, drug (s), permeation enhancer and additives, if any are required), casting the matrix over a coating or release boundary layer, removing the solvent from the matrix, and applying a layer. as the case may be. It will be appreciated by those skilled in the art that the matrix kit containing an effective amount of the drug dispersed therein can be used in a variety of transdermal constructs, and therefore applicants are not limited to the application forms of the invention described below.

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The following examples further illustrate the invention. These examples are not intended to limit the invention in any way. Unless otherwise stated, these percentages are by weight.

Example 1

Duro-Tak 87-2287 is a solution of a polyacrylate binder commercially available from National Starch and Chemical Co. Its monomer composition consists of: vinyl acetate, 2-ethylhexyl acrylate, hydroxyethyl acrylate and glycidyl methacrylate. It does not contain a cross-linking agent. It can be purchased as a 50% solids solution in ethyl acetate.

Mixtures of Duro-Tak 87-2287 were prepared with the addition of 0.26% aluminum acetylacetonate as crosslinker, 6% 17-d-Ngm, 1% EE and various permeation enhancers. These mixtures were cross-linked and poured as 100 micron (wet) layers over a 3M 1022 polyester coating and dried. Skin flow tests were performed on the side of the assemblies obtained using the procedure described in Chapter 7 of US Patent No. 5,252,334. HPLC was used for the determination of 17-d-Ngm and EE. The Perkin Elmer HPLC system was used with a Diedoarray detection unit at 245 nm and 251 nm for 17-d-Ngm and EE, respectively. The mobile phase was 55% water and 45% acetonitrile at a flow rate of 1.0 ml / min. The retention time was 4.5 and 3.0 min for 17-d-Ngm and EE, respectively. Details of the formulations and flow test results are given in Table 1 below.

Table 1

Preparation Flow (pg / cm ² / hour) 17-d-Ngm EE 2% TG + 4% OL 0.30 ± 0.04 0.061 ± 0.007 2% TG + 10% ML 0.39 ± 0.03 0.076 ± 0.005 2% TG + 10% PGML 0.29 ± 0.06 0.0571 ± 0.009 3% TG 0.24 ± 0.06 0.043 ± 0.011 4% TG + 15% ML 0.38 ± 0.001 0.072 ± 0.0002

TG = thioglycerin

ML = methyl laurate

OL = oleic acid

PGML = propylene glycol monolaurate

Example 2

Silicone 4202 is a polydimethylsiloxane binder from Dow Corning. It was mixed with 17-d-Ngm, EE, 7% PVP (K30 from BASF; dissolved in n-propanol) and various permeation enhancers. These mixtures were poured as 100 micron thick layers (wet) over a 3M 1022 polyester coating and dried. Skin flow tests were performed and the results of the flow test are shown in Table 2 below.

Table 2

Preparation Flow (pg / cm ² / hour) % 17-d-Ngm % EE Permeability enhancer 17-d-Ngm EE 1 2 3 4 5 4 0.5 5% ML + 1% TG 0.65 ± 0.009 0.069 ± 0.007 6 0.5 5% ML + 1% TG 0.60 ± 0.04 0.043 ± 0.004 6 0.5 14% PGML 0.48 ± 0.04 0.070 ± 0.01

181 582 cont. table 2

1 2 3 4 5 6 0.5 14% (TC: PGML; 80:20) 0.58 ± 0.05 0.062 ± 0.01 ♦ 4 0.5 4% TG + 5% ML 0.64 ± 0.01 0.078 ± 0.01 4 0.5 2% ML 0.51 ± 0.08 0.074 ± 0.008 2 0.5 2% TG + 2% ML 0.71 ± 0.09 0.18 ± 0.02

* Contains 14% PVP, not 7% PVP TC = Transcutanol

Example 3

Comparative testing of the silicone adhesive 17-d-Ngm and EE patches was performed using two types of PVP: low molecular weight soluble PVP, designated PVP-K30 from BASF, and insoluble cross-linked micronized PVP, designated PVP-CLM from BASF.

PVP-K30 was dissolved in anhydrous ethanol. Mixtures of 17-d-Ngm, EE and PVP-K30 were made and then silicone 4202 and methyl laurate were added. The mixture was stirred overnight. The mixture was then poured onto a layer of 3M 1022 as a 15 mil layer (wet) and dried at 70 ° C for 40 min.

PVP-CLM is available as a micronized solid. Silicone 4202 and PVP were mixed together and then methyl laurate, EE, 17-d-Ngm and ethanol were added. The mixture was stirred overnight, poured onto 3M 1022 and dried as above.

A skin flux test was performed on the kits described above as described in Example 1. Details of these formulations and the results of the flux tests are given in Table 3 below.

Table 3

Flow (pg / cm ² / hour) Preparation 17-d-Ngm EE 0.1% EE, 1% 17-d-Ngm, 5% ML, 7% PVP-CLM 86.9% silicone 0.49 ± 0.02 0.05 ± 0.002 0.1% EE, 1% 17-d-Ngm, 5% ML, 7% PVP-K30, 86.9% silicone 0.37 ± 0.07 0.04 ± 0.008

Example 4

PIB solutions were prepared by dissolving VISTANEX LI00, Vistanex LM-MS-LC and polybutene (INDOPOL H 1900) in hexane. PVC-CLM, 17-d-Ngm, EE and various permeation enhancers were suspended in ethanol / ethyl acetate. The PIB solution was added to the drug suspension and the resulting mixture was mixed. A 10 mil (wet) layer was then cast from this mixture on the release boundary layer and dried at 70 ° C for 40 min. The kit was laminated with a Saranex 2015 coating. The compounds were tested as described in Example 1. Details of these formulations and the results of the skin flux studies are given in Table 4 below.

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Table 4

Flow (pg / cm ² / hour) PIB * % EE % 17-d-Ngm % PVP-CLM % a permeation enhancer 17-d-Ngm EE 1: 5: 4 0.3 4.0 twenty 15. butyl sebacate 0.23 ± 0.02 0.06 ± 0.005 1: 5: 4 0.2 1.0 twenty 5. AMIFAT 0.32 ± 0.02 0.05 ± 0.004 1: 5: 4 0.2 4.0 twenty 5. Lauric acid Ν, Ν-dimethylamide 0.33 ± 0.02 0.04 ± 0.001 2: 4: 4 0.3 4.0 twenty 20. Propyl laurate 0.35 ± 0.09 0.06 ± 0.002 1: 5'4 0.2 2.0 twenty 5. lauroamido-diethanolamine 0.40 ± 0.05 0.06 ± 0.001 1: 5: 4 0.3 4.0 twenty 15. isopropyl palmitate 0.44 ± 0.06 0.07 ± 0.001 1: 5: 4 0.3 4.0 twenty 15. ethyl oleate 0.46 ± 0.06 0.10 ± 0.001 1: 5: 4 0.3 4.0 twenty 8. PGIS 0.48 ± 0.04 0.10 ± 0.001 1: 5: 4 0.2 2.0 twenty 3. oleic acid 0.60 ± 0.11 0.06 ± 0.002 1: 5: 4 0.2 3.0 twenty 3. oleic acid 0.60 ± 0.24 0.04 ± 0.002 1: 5: 4 0.2 2.0 twenty 10. PGML 0.59 ± 0.05 0.09 ± 0.001 1: 5: 4 0.2 3.0 twenty 10. PGML 0.67 ± 0.07 0.07 ± 0.001 1: 5: 4 0.3 4.0 twenty 8/3. PGML / oleic acid 0.79 ± 0.04 0.14 ± 0.001 1: 5: 4 0.2 2.0 twenty 10 / 0.5. PGML / oleic acid 0.68 ± 0.09 0.10 ± 0.001

* Weight ratio Vistanex L100: Vistanex LM-MS-LC: polybutene

AMIFAT is obtained from glycerin, oleic acid and 2-pyrrolidone-5-carboxylic acid PGIS = propylene glycoisostearate

Example 5

A preparation and matrix suitable for hormone replacement therapy were prepared as follows. 2% 17-β-estradiol. 2% deacetyl-norgestimate, 20% PVP-CLM and 76% PIB-based binder (1: 5: 2.5: 1.5 Vistanex L10Ó: Vistanex LM-MS-LC: polybutene: Zonester 85FG) were dissolved in the hexane mixture, ethyl acetate and ethanol. An appropriate release liner was then cast from this mixture and dried at 70 ° C for 45 minutes. A coating layer was applied prior to the flow test. A flow test was performed as described in Example 1.

Table 5

Steroids Flow (pg / cm ² / hour) 71-d-Ngm 0.10 71-p-estradiol 0.20

Example 6

Skin patches containing a matrix of PIB binder, PVP = CLM, lauryl or myristyl lactate, 17-d-Ngm and EE were made as follows:

17-d-Ngm and EE were dissolved in ethyl acetate and PVP-CL and lauryl lactate or myristyl lactate (obtained from ISP VanDYK, Belleville, NJ) were added to the solution. A solution of the PIB binder (1: 5: 4 Vistanex L100: Vistanex LM-MS-LC: Indopol H 1900) in hexane was added to the steroid solution with vigorous stirring. N-Propanol was added slowly to the final mixture, with 10% by weight of PVP-CLM. The mixtures were poured over a release liner and dried in an oven at 70 ° C for 40 minutes. The dried matrix weighed 7.5 mg / cm ² .

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The matrix-release limiter assembly was laminated with a polyester film (Scotchpak 1012). Another set was laminated with a layer of non-woven polyester (Remay 2250). The release liner was removed from the coated assembly and applied to the nonwoven liner assembly to form a 5-layer composite comprising a coating layer / adhesive matrix / nonwoven fabric / adhesive matrix / release liner.

The skin flux test of these patches was performed as described in Example 1. Details of the patches and the results of the flux tests are given in Table 6 below.

Table 6

Matrix preparation Skin permeability Flow 17-d-Ngm pg / cm ² / hour Flow EE pg / cm ² / hour 72.85% PIB small 0.23 0.02 20% PVP-CLM mean 0.45 0.05 0.15% EE big 0.82 0.08 5% lauryl lactate 70.8% PIB small 0.20 0.03 20% PVP-CLM mean 0.55 0.08 0.2% EE 2% 17-d-Ngm 7% lauryl lactate 72.8% PIB - 0.64 0.09 20% PVP-CLM 0.2 EE 2% 17-d-Ngm 5% myristyl lactate

Modifications to the above-described methods for carrying out the invention that will be apparent to those skilled in the art of skin patches are understood to fall within the scope of the following claims.

Claims (29)

A skin patch for preventing ovulation in a woman, comprising a coating layer and a matrix layer under the coating layer, characterized in that the matrix layer consists of a mixture of 17-deacetylnorgestimate, a pressure-sensitive adhesive containing at least silicone or polyisobutylene, and optionally a booster skin permeability. 2. The patch according to claim 1 The method of claim 1, wherein the dose of 17-deacetyl-norgestimate is 175 to 300 pg / day. 3. The patch according to claim 1 The process of claim 1, wherein the pressure-sensitive adhesive is polyisobutylene. 4. The patch according to claim 1 The method of claim 1, wherein the matrix layer comprises a skin permeation enhancer. 5. A patch according to claim 1 4, characterized in that as a means of enhancing permeability through the skin comprises an agent selected from the group consisting of lactate esters of aliphatic alcohols C ₁₂ to C _g, oleic acid and PGML. 6. A patch according to claim 1 The process of claim 5, wherein the skin permeation enhancer is lauryl lactate. 7. A skin patch for preventing ovulation in a woman comprising a coating layer, and a matrix layer under the coating layer, characterized in that the matrix layer consists of a mixture of 17-deacetylnorgestimate, an estrogen, a pressure-sensitive adhesive containing at least silicone or polyisobutylene and optionally an agent enhancing skin permeability. 8. A patch according to claim 1 The process of claim 7, wherein the pressure-sensitive adhesive comprises polyisobutylene. 9. A patch according to claim 1 The method of claim 8, wherein the matrix layer comprises a skin permeation enhancer. 10. A patch according to claim 1 The process of claim 9, wherein the estrogen is estradiol. 11. A patch according to claim 1 The method of claim 10, wherein the estradiol is ethinylestradiol or 17-p-estradiol. 12. A patch according to claim 1 A process as claimed in claim 11, characterized in that the estradiol is ethinylestradiol. 13. A patch according to claim 1 The method of claim 12, characterized in that the dose of 17-deacetyl-norgestimate in an amount of 175 to 300 pg / day and of ethinyl estradiol in an amount of 10 to 35 pg / day. 14. A patch according to claim 1 The process of claim 11, wherein the estradiol is 17- [3-estradiol. 15. A patch as claimed in claim 1 The method of claim 14, wherein the dose of 17-deacetyl-norgestimate is 175 to 300 pg / day and the dose of 17-fyestradiol in an amount of 30 to 150 pg / day. 16. A patch according to claim 16 11, characterized in that as a means of enhancing permeability through the skin comprises an agent selected from the group consisting of lactate esters of aliphatic alcohols C ₁₂ to C _g, oleic acid and PGML. 17. A patch according to claim 1 The process of claim 16, wherein the skin permeation enhancer is lauryl lactate. 18. A skin patch for the delivery of hormone replacement therapy for a woman, comprising a coating layer and a matrix layer under the coating layer, characterized in that the matrix layer consists of a mixture of 17-deacetyl-norgestimate, estrogen, a pressure-sensitive adhesive containing at least silicone or polyisobutylene, and optionally a skin permeation enhancer. 181 582 19. A patch as claimed in claim 1 The process of claim 18, wherein the pressure-sensitive adhesive is polyisobutylene. 20. A patch according to claim 1 19. The process of claim 19, wherein the matrix layer comprises a skin permeation enhancer. 21. A patch according to claim 1 The process of claim 20, wherein the estrogen is estradiol. 22. A patch according to claim 1 A process as claimed in claim 21 in which the estradiol is ethinylestradiol or 17-p-estradiol. 23. A patch according to claim 1 A pharmaceutical composition according to claim 22, characterized in that the estradiol is ethinylestradiol. 24. A patch according to claim 24 The method of claim 23, characterized in that the dose of 17-deacetyl-norgestimate in an amount of 175 to 300 pg / day and of ethinyl estradiol in an amount of 10 to 35 pg / day. 25. A patch according to claim 1 A process according to claim 22, characterized in that the estradiol is 17-β-estradiol. 26. A patch according to claim 1 The method of claim 25, characterized in that the dose of 17-deacetyl-norgestimate in an amount of 175 to 300 pg / day and a dose of 17-β-estradiol in an amount of 30 to 150 pg / day. 27. A patch according to claim 1 22, characterized in that as a means of enhancing permeability through the skin comprises an agent selected from the group consisting of lactate esters of aliphatic alcohols C ₁₂ to C _g, oleic acid and PGML. 28. Patch according to claim 27 wherein the skin permeation enhancer is lauryl lactate. 29. A skin patch for preventing ovulation in a woman comprising a coating layer and a matrix layer beneath the coating layer characterized in that the matrix layer consists of a mixture of 17-deacetyl norgestimate, a pressure-sensitive polyisobutylene binder and polyvinylpyrrolidone.